Indoles which have steroid 5-α reductase inhibitory activity

Abstract

PCT No. PCT/EP93/00380 Sec. 371 Date Aug. 2, 1994 Sec. 102(e) Date Aug. 2, 1994 PCT Filed Feb. 16, 1993 PCT Pub. No. WO93/17014 PCT Pub. Date Sep. 2, 1993The present invention provides compounds of the formula: <IMAGE> (I) and the pharmaceutically acceptable salts thereof, together with pharmaceutically compositions containing, uses of, processes for the preparation of and intermediates used in the preparation of, such compounds.

What is claim is: 
     
       1. A compound of the formula: ##STR162## or a pharmaceutically acceptable salt thereof, wherein X is O, NH, N(C 1  -C 4  alkyl), direct link, C 1  -C 4  alkylene, C 2  -C 4  alkenylene or C 2  -C 4  alkynylene, said alkylene, alkenylene and alkynylene being optionally substituted by C 1  1∝C 4  alkyl or aryl;   Y is methylene, C 2  -C 6  alkylene optionally interrupted by O, C 2  -C 6  alkenylene or C 2  -C 6  alkynylene, all of which may be optionally substituted by C 1  -C 6  alkyl, or is a group of the formula: ##STR163## wherein m and n are each independently selected from O and an integer of from 1 to 5, with the proviso that the sum of m and n is not greater than 5, and p is an integer of from 2 to 6;   R is H, OH, halo, C 1  -C 4  alkyl or C 1  -C 4  alkoxy;   R 1 , R 2 , R 3  and R 4  are each independently selected from H, C 1  -C 4  alkyl, C 1  -C 4  alkoxy, OH, halo, --CF 3 , --CO 2  (C 1  -C 4  alkyl), --CONH 2 , --CONH(C 1  -C 4  alkyl) and --CON(C 1  -C 4  alkyl) 2  ;   R 5  is --COOH, --COOR 7 , --CONR 8  R 9  or tetrazol-5-yl;   R 6  is ##STR164## R 7  is a biolabile ester-forming group; R 8  and R 9  are each independently selected from H and C 1  -C 4  alkyl;   R 10 , R 11  and R 12  are each independently selected from H, C 1  -C 4  alkyl, C 1  -C 4  alkoxy, --OH, halo and halo(C 1  -C 4  alkyl);   R 13  and R 14  are each independently selected from H, C 1  -C 10  alkyl, C 1  -C 10  alkoxy, C 2  -C 6  alkenyl, C 2  -C 6  alkynyl, C 3  -C 8  cycloalkyl, --CO 2  (C 1  -C 4  alkyl), --CONR 8  R 9 , --CN, halo(C 1  -C 6  alkyl), aryl and heteroaryl, said alkyl and alkoxy groups being optionally substituted by C 1  -C 6  alkoxy, C 3  -C 7  cycloalkyl, --OH, --CO 2  (C 1  -C 4  alkyl), -CONR 8  R 9 , -CN, aryl, aryloxy or heteroaryl, and said alkenyl and alkynyl groups being optionally substituted by aryl, with the proviso that R 13  and R 14  are not both H, or R 13  and R 14 , taken together with the carbon atom to which they are attached, represent optionally benzo-fused spiro(C 3  -C 8 )cycloalkane, said spirocycloalkane group and the benzo-fused portion being optionally substituted by C 1  -C 6  alkyl, C 1  -C 6  alkoxy, C 3  -C 8  cycloalkyl, --OH, --CO 2  (C 1  -C 4  alkyl), --CONR 8  R 9 , --CN, halo(C 1  -C 6  alkyl), aryl or heteroaryl, or R 13  and R 14 , taken together with the carbon atom to which they are attached, represent spiropyrrolidine or spiropiperidine, both of which may be optionally N-substituted by C 1  -C 6  alkyl, C 2  -C 6  alkanoyl, C 2  -C 6  alkanoyl(C 1  -C 4  alkyl)- or arylcarbonyl;   "aryl" used in the definitions of X, R 13  and R 14  means phenyl optionally substituted by C 1  -C 6  alkyl, C 1  -C 6  alkoxy, C 2  -C 6  alkenyl, OH, halo, halo(C 1  -C 6  alkyl), nitro, amino, C 2  -C 6  alkanamido, C 2  -C 6  alkanoyl, --CO 2  (C 1  -C 4  alkyl), phenyl, phenyl(C 1  -C 4 )alkoxy or --(CH 2 ) q  CONR 8  R 9  wherein q is O or an integer of from 1 to 4;   and "heteroaryl" used in the definitions of R 13  and R 14  means a five- or six-membered heteroaromatic group which contains from 1 to 4 heteroatoms each independently selected from N, O and S and which is optionally substituted by C 1  -C 4  alkyl, C l  -C 4  alkoxy, halo, --OH or halo(C 1  -C 4  alkyl).   
     
     
       2. A compound as claimed in claim 1 wherein X is a direct link or C 1  -C 4  alkylene,   Y is C 1  -C 6  alkylene,   R is H or C 1  -C 4  alkyl,   R 1 , R 2 , R 3  and R 4  are each H,   R 5  is --COOH or --COO(C 1  -C 6  alkyl),   R 6  is ##STR165## R 10 , R 11  and R 12  are as defined in claim 1 and R 13  and R 14  are each independently selected from H, C 1  -C 10  alkyl optionally substituted by C 1  -C 6  alkoxy, C 2  -C 6  alkynyl, C 3  -C 8  cycloalkyl, phenyl optionally substituted by C l  -C 6  alkyl, C 1  -C 6  alkoxy, halo, halo(C 1  -C 6  alkyl) or phenyl(C 1  -C 4 )alkoxy, thienyl and furyl, or R 13  and R 14 , taken together with the carbon atom to which they are attached, represent optionally benzofused spiro(C 5  -C 7 )cycloalkane, optionally substituted by --CN or phenyl.   
     
     
       3. A compound as claimed in claim 2 wherein X is a direct link or methylene,   Y is ethylene, propylene or butylene,   R is H or methyl,   R 5  is --COOH or --CO 2  C 2  H 5 ,   R 10 , R 11  and R 12  are each H and   R 13  and R 14  are each independently selected from H, methyl, ethyl, n-propyl, n-butyl, t-butyl, 3-methoxyprop-1-yl, 1-propynyl, cyclohexyl, phenyl, 4-methylphenyl, 4-ethylphenyl, 4-(n-propyl)phenyl, 4-(2-methylpropyl)phenyl, 3,4-dimethylphenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-methoxyphenyl, 4-trifluoromethyl-phenyl, 4-benzyloxyphenyl, cyclohexyl, 2-thienyl and 2-furyl,   or R 13  and R 14 , taken together with the carbon atom to which they are attached, represent spirocyclohexane, spirocycloheptane, or a group of the formula: ##STR166## where * represents the spiro carbon atom in common with the 1,3-benzodioxolane ring.   
     
     
       4. A compound as claimed in claim 3 wherein X is a direct link, Y is propylene, R is H,   R 5  is --COOH or --CO 2  C 2  H 5 ,   R 13  is methyl and R 14  is 4-(2-methylpropyl)phenyl.   
     
     
       5. A compound as claimed in claim 1 wherein R 5  is --COOH. 
     
     
       6. A compound as claimed in claim 1 which is (-)-4- 3-( 2-methyl-2-(4- 2-methylpropyl!phenyl)-1,3-benzodioxolan-5-yl!carbonyl)indol-1-yl!butanoic acid and (-)-ethyl 4- 3-( 2-methyl-2-(4- 2-methylpropyl!phenyl)-1,3-benzodioxolan-5-yl!carbonyl)indol-1-yl!butanoate, or a pharmaceutically acceptable salt of either thereof. 
     
     
       7. A compound as claimed in claim 1 wherein the pharmaceutically acceptable salt is the sodium, potassium, N-benzyl-N-(2-phenylethyl)amine or 1-adamantylamine salt. 
     
     
       8. A pharmaceutical composition comprising an amount of a compound according to claim 1 effective in inhibiting steroid 5-alpha reductase, together with a pharmaceutically acceptable diluent or carrier. 
     
     
       9. A method of treatment of a human to inhibit a steroid 5α-reductase which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof, as claimed in claim 1. 
     
     
       10. A method of treatment of a human for acne vulgaris, alopecia, seborrhoea, female hirsutism, benign prostatic hypertrophy, male pattern baldness or a human prostate adenocarcinoma which comprises treating said human with an effective amount of a compound of the formula (I) or with a pharmaceutically acceptable salt or composition thereof, as in claim 1. 
     
     
       11. A compound of the formula: ##STR167## wherein R 16  is H or C 1  -C 4  alkyl, R 24  is H or OH, R 25  is ##STR168##  and X, Y, R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 10 , R 11  and R 12  are as defined in claim 1 for a compound of the formula (I).   
     
     
       12. A compound of the formula (VIII) as claimed in claim 11 which is 3-( 2-methyl-2-(4- 2-methylpropyl!phenyl)-1,3-benzodioxolan-5-yl!carbonyl)indole or (-)-3-( 2-methyl-2-(4- 2-methylpropyl!phenyl)-1,3-benzodioxolan-5-yl!carbonyl)indole, or a base salt of either thereof. 
     
     
       13. 2-Methyl-2- 4-(2-methylpropyl)phenyl!-1,3-benzodioxolane-5-carboxylic acid, or (-)-2-methyl-2- 4-(2-methylpropyl)phenyl!-1,3-benzodioxolane-5-carboxylic acid or the (-)-α-methylbenzylamine salt thereof. 
     
     
       14. A pharmaceutical composition comprising an amount of a compound according to claim 1 effective in inhibiting steroid 5-alpha reductase for treating a condition selected from acne vulgaris, alopecia, seborrhea, female hirsutism, benign prostatic hypertrophy, male pattern baldness, and human prostate adenocarcinoma, together with a pharmaceutically acceptable diluent or carrier.